Introduction
Children with cancer are treated in many different ways. Surgery, chemotherapy, radiation therapy, immunotherapy (antibodies, cytokines, hormones, biologic agents) and bone marrow/stem cell transplantation are the main methods of treatment. They are used singly or in combination. The good news is that children with cancer have a high cure rate. This is because of research and continued improvement in therapy. But this also means that therapy for cancer continues to increase in intensity and side effects. Survivors of cancer, their family and friends, and primary physicians should be aware of these side effects. This will help to understand and identify problems a survivor of cancer may encounter. He or she should seek appropriate follow up and early help when necessary. Many side effects are controlled or improved with intervention. The goal is to return patients as quickly and effectively as possible back to their normal lifestyle.

Side effects occur because the treatment that is used to kill cancer cells also attacks normal cells in the body to a variable extent. Organs that are growing with the child and normal cells that are very active or multiplying rapidly are affected the most. Sometimes the damage is permanent but may or may not cause a significant problem. It is not possible to list every drug and side effect, but I have tried to list the common drugs and describe common problems, focusing more on the late side effects.

Side effects are related to the (1) location and type of the cancer (2) age at treatment and (3) length, type and intensity of treatment. Thus, widespread cancer or recurrent disease will need more intense therapy and hence have more side effects. Therapy is directed at effectively removing the cancer while trying to keep side effects minimal.

Early side effects of chemotherapy at completion of therapy
These include increased susceptibility to infection, low blood counts, lassitude, nausea, loss of appetite, soreness in the mouth, throat and stomach, hair loss, patches and lines in the nails, darkening of the skin, sensitivity to sunburn, neuropathy, constipation or diarrhea, fluid and electrolyte imbalance, etc. In most cases, they can be expected to improve gradually and return to normal within 3-4 months after treatment is completed.

Side effects of surgery
Surgical removal of a tumor can leave behind cosmetic changes or handicaps that are directly related to the location of the surgery. Children with brain tumors may have significant damage to their brain at diagnosis. The surgeon may have to remove some normal brain tissue to completely remove a tumor. This may result in problems with sight, speech, hearing, movement, strength, learning, hormone or fluid/salt imbalance and seizures depending on the location and extent of damage. Some of these effects may become obvious only as the child grows or starts school, and may be worsened by radiation. Children will require periodic assessment for at least one year to detect such problems and commence rehabilitation or hormone replacement if necessary. Prior to starting school they should again have detailed assessment for the early detection of learning disabilities so that they may receive special education if necessary.

Surgery of structures around the face may require reconstruction and correction of deformities later for cosmetic reasons. Bone tumors in the arms or legs may require amputation or tumor removal and the use of external or internal prostheses that have to be adjusted with growth. Bone damage and growth will need to be closely monitored. Removal of tumors without amputation may result in weakness, restriction of movement or decreased growth of a limb. Close medical observation and intervention are necessary.

Removal of the stomach, pancreas or intestines may require diet modifications if absorption and digestion of food or essential vitamins is affected. Surgery in the abdomen and pelvis can result in late hernias, adherence, obstruction and twisting of the gut causing pain and other bowel symptoms. Removal of the spleen makes patients susceptible to bacterial infections that could become serious and needs timely care.

Side effects of surgery will become apparent immediately after surgery so that the necessary intervention can be planned early. Occasionally surgery can cause late problems (a few months later), such as narrowing/tethering of the intestines (abdominal surgery) resulting in vomiting, constipation or pain, decreased food intake or absorption/diarrhea, etc. and will need to be treated by a doctor.

Late side effects
The side effects described below develop gradually over a period of time. They are related to radiation, chemotherapy or bone marrow transplantation. Radiation therapy: The dose, extent and location of radiation determine side effects.

Radiation therapy to the brain can affect movement, coordination, intelligence and learning especially in young children with developing brains. Children less than 3 years old are most affected. Between 3 and 6 years there is less risk of damaging brain function. The risk is even lower in children older than 6 years at the time of radiation. Baseline developmental testing is done prior to radiation therapy and continued after completion to plan appropriate intervention at home and school and seek special services if necessary. Hormone production may be affected by radiation therapy to the pituitary gland (at base of brain), affecting growth, salt/fluid balance, sex hormone levels, etc.

Radiation therapy to the head or face can result in drying and irritation of the eyes and requires the use of artificial tears. Cataracts may develop. Radiation therapy in the region of the mouth or throat may cause a dry mouth, stone formation in the salivary glands or affect the growth of the jaws or destroy the jawbone. Dental problems are common and need regular follow up with a dentist. Taste, eating and bowel habits, or food absorption may be affected.

Thyroid function is decreased after neck and chest radiation resulting in weight gain, cold intolerance, etc.. Radiation therapy to the chest can result in defective lung or heart function. These need monitoring, therapy and advice regarding restriction of activity, increased workload during pregnancy, etc.

The adrenal gland, ovaries and testes can have decreased function after radiation to the abdomen, pelvis and testes. Cortisol and sex hormone levels, the onset of puberty, etc. will need to be regularly assessed at follow up and hormones supplemented if necessary. Radiation to the abdomen can affect the kidneys and may result in increased blood pressure.

Bone growth is slowed by radiation therapy and can result in short stature (whole body or spine radiation) or decrease growth of isolated bones affected by radiation such as the teeth, jaws or a limb. Limitation of movement occurs if joints or muscles are affected. Some of these require medical or surgical correction if the side effects are significant. Skin is sensitive to sunburn following radiation. Regular use of sunscreen is essential.

Finally, radiation therapy results in an increased incidence of second cancers especially at a previously radiated site and should always be ruled out medically if unexplained symptoms develop. Routine screening in specific areas to detect a second cancer early is a good idea. Examples are: Examination of the neck and thyroid gland or regular mammograms starting in the twenties to detect breast cancer developing in women after radiation to the chest.

Chemotherapy: All chemotherapy agents generally have early side effects that subside over a period of weeks to months after therapy is completed. Several groups of chemotherapy agents also have specific late effects developing over months to years after treatment is completed. They are agent and dose dependent. Some of the common effects are listed below.

Alkylating agents: Include a large number of drugs and are grouped together based on common side effects. All alkylating agents can cause infertility by decreasing the production of sperms and eggs. They can also cause early menopause if fertility is preserved, so that the number of reproductive years are fewer. They also alter normal cells and predispose to the development of late second cancers. These cancers are usually acute leukemia or lymphoma but any tumor can occur. It is necessary to monitor for bone marrow dysfunction, changes in blood counts, etc. to detect the development of blood cell abnormalities.

1. Cyclophosphamide and ifosfamide: They can decrease kidney function and impair absorption of essential nutrients such as potassium, bicarbonate and phosphorus, or excretion of toxic waste substances such as urea and creatinine (kidney failure). They can cause damage and scarring of the urinary bladder. This can result in an urge to urinate frequently and cause blood and clots in the urine. Rarely the bladder has to be removed and urine surgically diverted.
2. Mustargen, BCNU, CCNU, melphalan: They can cause decreased lung function and volume. Kidney damage may occur and needs to be evaluated at follow up.
3. Cisplatin and carboplatin: They can cause decreased kidney function. The kidney may be unable to absorb magnesium so body magnesium levels become low and need to be supplemented. Hearing can be affected, especially with cisplatin. Hearing aids may become necessary if hearing tests are abnormal. This should be done early especially in a young child who is just learning to talk or in a child having school problems because of hearing difficulties.
4. Procarbazine and dacarbazine: Can cause infertility or increase the chances of miscarriage and still birth. There is no evidence that babies will be born deformed in any way because a parent received chemotherapy. Liver damage can occur, especially in combination with other agents that damage the liver.
5. Thiotepa: Can cause sterility and predisposes patients to the development of second cancers.
6. Busulfan: Can cause decreased lung function or liver damage. Long term monitoring is required.

Natural products:

1. Actinomycin D: By itself this drug has few late side effects. If used in combination with radiation therapy, it can increase the local side effects of radiation and cause increased skin inflammation and rash that eventually subsides with time. In combination with radiation and other therapeutic agents, it can accentuate damage to organs such as the lungs, heart, gastrointestinal tract, liver and kidney.
2. Anthracyclines: Examples are daunomycin, doxorubicin, idarubicin and mitoxantrone. They affect heart muscle growth and function and can cause defective heart function or heart failure. The heart may thus be unable to cope with excess demand especially with aggressive exercise or the extra demands of pregnancy. Regular follow up of heart function by EKG and/or echocardiogram is important to detect and treat these complications on time. Some symptoms of heart problems are excessive tiredness, shortness of breath, chronic cough that wonít go away and palpitation (being aware of regular or uneven heartbeats even at rest). Anthracyclines can augment radiation therapy damage like actinomycin D can. When combined with other agents, damage to the liver, gastrointestinal tract, lungs and kidney is increased.
3. Bleomycin: Causes fibrosis in the lungs and results in shortness of breath, poor exercise capacity, etc. These effects are enhanced by radiation to the chest. Pulmonary functions should be serially tested for early detection and treatment.
4. L-asparaginase: Can cause permanent damage to the pancreas and cause decreased digestive enzymes and diabetes. The drug increases the chances of developing clots within blood vessels and can cause clotting in the arms and legs but also permanent damage to vital organs such as the brain due to clot formation and decreased blood supply.

Antimetabolites:

1. Cytosine arabinoside (Ara-C): Can affect the central nervous system and cause weakness, seizures and altered consciousness especially when instilled in the spinal fluid or given in high doses.
2. Methotrexate: When instilled into the nervous system or given repeatedly as a high dose intravenously, methotrexate can cause learning disabilities especially in the young child. Serial testing is necessary to plan adequate intervention especially in school. Methotrexate can also precipitate seizures or have other manifestations of brain damage. It can also cause permanent scarring of the liver and kidney damage. Bones are weaker, and have less calcium when methotrexate is used for prolonged periods. Rarely, bones may undergo degeneration, causing pain, fractures or joint problems. All these need to be carefully monitored during and after methotrexate based therapy.
3. 6 mercaptopurine: Negligible long term side effects.
4. VP16 (etoposide), VM26 (teniposide): These drugs in high doses or with prolonged therapy predispose to the development of altered bone marrow function causing anemia, bleeding and infections. This can progress to become leukemia.

Hormones:

Steroids: Steroid use for long periods can cause cataracts in the eyes that will need to be surgically removed. The adrenal gland that normally produces essential steroids may stop doing so with long term steroid use and may never recover. Since this hormone is essential at times of stress to the body (such as surgery), supplementation may become necessary. Steroids also can weaken bones, alter growth, and affect bones around the hip joint causing a painful condition called ëavascular hip necrosisí that will need orthopedic intervention. Continued steroid use can cause weight gain, high blood pressure and diabetes that need medical attention.

Stem cell transplantation: High dose chemotherapy and/or radiation therapy is usually necessary before infusing stem cells for transplantation. Hence, all the side effects described above such as infertility and second cancers are more common and severe in transplant patients. If bone marrow or stem cells were infused from another person, they can cause graft versus host disease. This can affect different organs and needs continued medical attention. Muscle weakness, joint stiffness or skin rash and thickening may occur because of radiation or graft versus host disease. Physical and occupational therapy and guidance in addition to medical treatment can help. This may require special services especially in school and should be requested as needed. Various organ functions such as eyes, lung, liver, gut and kidneys need to be serially monitored after transplantation. The immune system does not function well for many months or even years after a bone marrow transplant, especially when there is graft versus host disease, and all infections should be promptly and adequately treated.

Cyclosporine: Can cause seizures, high blood pressure, increased body hair and anemia especially with prolonged use. Kidneys may not function well. It decreases function of cells of the immune system called lymphocytes increases the chances of fungal and viral infections. It may predispose to the development of lymphomas (tumors) because of this immune suppression.

Additional side effects of therapy

The immune system and infection: Radiation and chemotherapy temporarily (for about 3-6 months) destroy the immune system and care should be taken to avoid contact with infectious situations. Following transplantation, the immune system takes longer to recover (6 months to 1 year) especially if graft versus host disease is present. Preventive medicines may be necessary after cancer treatment is completed. Infections also need early diagnosis and aggressive treatment. Vaccines are not given during treatment and vaccination should be resumed after treatment is completed (usually after 6 months to 1 year) based on medical advice.

Psychosocial and adjustment problems: Survivors of cancer need a lot of support and empathy from family and friends and yet should be allowed gradually to return to a normal lifestyle. Concerns about appearance, growth, learning disabilities, dental problems, sexual dysfunction and infertility may result in emotional stress that should be handled with the right amount of support and understanding. Medications may be of benefit medical consultation should be sought on time. In addition, interaction with support groups can help to relate better to side effects and handicaps.

Second cancers: Though most cancers are not hereditary and never infectious, there are some genetic disorders known as ëcancer predisposition syndromesí that are associated with repeated cancers in different locations within one individual and similarly affected members of the family. Because of the risk of second cancers either for genetic reasons or due to radiation and chemotherapy, regular medical follow up is wise and any unusual symptoms such as easy bruising or bleeding, swelling or skin lesions should be immediately investigated.

Excess weight gain: The loss of appetite and nausea that occur during therapy of cancer go away and appetite returns to normal gradually after therapy is completed. This can result in excess food intake and may be combined with restricted physical activity. This can frequently result in excess weight gain and obesity. A dietician will be able to advise regarding a healthy diet suitable for age and activity.

Symptoms Based on Organs Affected

Conclusion:

There are many side effects of cancer therapy. But most of these are relatively minor compared to the cancer. They can often be prevented, controlled or improved if anticipated and detected early. Hence, an awareness of the late side effects of cancer therapy is essential for cancer survivors as well as their friends, family and care givers. Regular, long term medical follow up as well as social support is as important as treating the cancer.

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